Alzheimer's disease is a degenerative disorder of the central nervous system that results in a progressive loss of memory and other intellectual functions, such as reasoning, orientation, and judgement (R. Katzman, Banbury Report 15: Biological Aspects of Alzheimer's Disease, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., (1983)). Alzheimer's disease occurs in sporadic and familial forms, and in the United States, affects about 600 people for every 100,000. A characteristic aspect of the neuropathology of the disease is the occurrence of proteinaceous deposits referred to as "amyloid" in the cores of brain lesions called neuritic or senile plaques, as well as in cerebral blood vessels. The "amyloid" deposits are generally defined as 6-10 nm protein filaments with certain staining properties (Abraham, C.R. et al., Cell, 52:487-501 (1988)).
Amyloid deposits are also found in the brains of aged humans, although not as extensively as in Alzheimer's disease. Further, Down's syndrome patients more than 30 or 40 years old invariably develop the symptoms and neuropathology characteristic of Alzheimer's disease.
One component of the amyloid deposits was identified as A4 amyloid or .beta.-protein (.beta.-protein) and is 42 amino acids long (Glenner, G.G and C.G. Wong, Biochem. Biophys. Res. Commun. 120:885-890 (1984)). This protein is apparently derived from a larger membrane-spanning precursor protein whose RNA is alternately spliced to yield several protein products (Selkoe, D.J., Science, 248:1058-1060). These observations suggested that the amyloid deposits in Alzheimer's disease could result from abnormal expression or posttranslational modification or processing of a normal molecule. Also intriguing was the finding that the gene encoding the amyloid protein precursor is located on chromosome 21, suggesting a common cause for the the deposits observed in Down syndrome, caused by trisomy of chromosome 21, and Alzheimer's disease.
As mentioned above, some cases of Alzheimer's disease appear to be familial, and are inherited in an autosomal dominant fashion. Linkage analysis in four families pointed to a lesion on the long arm of chromosome 21 (St. George-Hyslop, P.H. et al., Science, 238:664-660 (1987)), which correlated well with the mapping data and similarities between Down syndrome and Alzheimer disease. Recently, hereditary cerebral hemorrhage with amyloidosis of Dutch origin was reported to be linked to the APP gene, and a point mutation in the coding region of the gene was identified (Van Broeckhoven, C. et al. Science, 248:1120-1122 (1990); Levy, E. et al., Science, 248:1124-1126 (1990)). Patients with this disease have a form of the .beta.-protein in amyloid deposits in meningeal and cerebral blood vessels.
However, other studies reported linkage of familial Alzheimer's disease to a locus on chromosome 21 distinct from the amyloid precursor protein (APP) gene (Tanzi, R.E. et al, Nature, 329:156-157 (1987); Van Broeckhoven, C. et al., Nature, 329:153-155 (1987)). Furthermore, there was no evidence of duplication of the APP gene in cases of familial or sporadic disease. In fact, studies of some families reportedly indicate no linkage to chromosome 21 (Schellenberg, G.D., Science, 241:1507-1510, (1988). These data suggest that there may be genetic heterogeneity in the cause of inherited forms of Alzheimer's disease, and other locations for the disease gene have been proposed, such as chromosome 14 (Weitkamp, L.R., Amer. J. Hum. Genet. 35:443-453 (1983)).
Thus, other components of the proteinaceous deposits in Alzheimer's disease may also be of interest and may provide clues to the cause or progress of the disease. In fact, a second component of the amyloid deposits has been characterized as .alpha..sub.1 -antichymotrypsin (ACT), which, interestingly, is located on chromosome 14. Abraham et al. reported the identification of the serine protease inhibitor ACT in amyloid deposits in Alzheimer's disease brain. (Abraham, C.R. et al., Cell 52:487-501 (1988).